Obese humans exhibit enhanced decrements in pulmonary function following exposure to ozone (O3), an air pollutant, yet the mechanisms underlying this phenomenon are poorly understood. Consistent with human data, we demonstrate that obese mice exhibit increased airway responsiveness to methacholine following O3 exposure. Obesity-related sequelae are mechanistically linked to obesity-induced elevations in circulating adipokines, which are cytokines, chemokines, hormones, and soluble cytokine receptors that are largely pro- inflammatory. Of the pro-inflammatory adipokines increased in obesity, our data suggest that visfatin, a ubiquitous intracellular enzyme that functions as a pro-inflammatory cytokine when present in the extracellular space, may enhance O3-induced lung dysfunction in obesity. Our data demonstrate that (1) bronchoalveolar lavage fluid visfatin is greater in O3-exposed obese as compared to O3-exposed wild-type mice, (2) inhibition of the enzymatic activity of visfatin, which shares many pro-inflammatory effects with extracellular visfatin, a cytokine, decreases O3-induced pulmonary inflammation in wild-type mice. Extracellular visfatin increases nicotinamide adenine dinucleotide (NAD+), a coenzyme, and elevations in cytosolic NAD+ activate poly(ADP-ribose) polymerase (PARP)-1, an enzyme that promotes inflammation. In response to diverse inflammatory stimuli, PARP-1 is necessary for the maximal expression of cytokines and chemokines that contribute to O3-induced airway hyperresponsiveness and/or O3-induced pulmonary inflammation, cytosolic levels of including interferon ?-induced protein (IP)-10, interleukin (IL)-6, macrophage inflammatory protein (MIP)-2, and tumor necrosis factor (TNF)-?. Alveolar macrophages express PARP-1, are an abundant source of these aforementioned cytokines and chemokines, and contribute to O3-induced lung pathology. Furthermore, our preliminary data demonstrate that visfatin can stimulate the release of IP-10, IL-6, MIP-2, and TNF-? from MH- S cells, an alveolar macrophage cell line. Based on these observations, we shall test the central hypothesis that obesity enhances decrements in pulmonary function induced by exposure to O3 through extracellular visfatin-induced augmentation of pulmonary inflammation via PARP-1 activation in alveolar macrophages. We propose two Specific Aims to test this hypothesis. In Aim 1, we shall examine the role of extracellular visfatin in the development of increased airway responsiveness to methacholine and increased pulmonary inflammation in obese mice following exposure to O3 through the use of an anti-visfatin neutralizing antibody. In Aim 2, we shall examine the ability of visfatin to stimulate the release of cytokines and chemokines, which mediate O3-induced lung pathology, from MH-S cells in the presence of a PARP-1 inhibitor. In summary, these studies will provide a molecular mechanism by which extracellular visfatin exacerbates O3-induced lung dysfunction in obesity as well as novel pre-clinical data supporting the use of an anti-visfatin antibody as a therapeutic modality for the treatment of exaggerated lung dysfunction induced by O3 in obesity.